Testosterone attenuates pulmonary epithelial inflammation in male rats of COPD model through preventing NRF1-derived NF-κB signaling.
Testosterone attenuates pulmonary epithelial inflammation in male rats of COPD model through preventing NRF1-derived NF-κB signaling.
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睾酮通过阻止 NRF1 衍生的 NF-B 信号传导减轻 COPD 模型雄性大鼠的肺上皮炎症
DOI：
10.1093/jmcb/mjaa079
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发表时间：
2021-05-07
影响因子：
5.5
通讯作者：
Zhu L
中科院分区：
文献类型：
--
作者：
Wang X;Huang L;Jiang S;Cheng K;Wang D;Luo Q;Wu X;Zhu L
睾酮缺乏在患有慢性阻塞性肺疾病（COPD）的男性患者中是常见的，并且可能与COPD的恶化相关。临床研究表明，睾酮替代治疗可能延缓COPD的进展，但具体的生物学途径尚不清楚。本研究探讨睾酮对雄性COPD大鼠肺部炎症的影响。用脂多糖（LPS）和香烟共同处理动物以诱导COPD。在COPD大鼠中，核呼吸因子1（NRF 1）和NF-κB p65表达上调。在香烟烟雾提取物（CSE），LPS，或CSE和LPS的组合处理的L132细胞，NRF 1和p65也上调。沉默NRF 1导致p65的下调。ChIP双链测序、ChIP双链qPCR和荧光素酶结果显示NRF 1转录调控p65。雄性和雌性COPD大鼠均表现出上调的NRF 1水平和相似的肺形态。但NRF 1在雄性去势大鼠中进一步上调。进一步补充睾酮在去势雄性大鼠显着减少NRF 1，肺部病变和炎症。补充睾酮还可降低LPS或CSE诱导的L132细胞p65和IKKβ的磷酸化。我们的研究结果表明，睾酮通过抑制NRF 1源性NF-κB信号和p65磷酸化在COPD肺上皮炎症中发挥保护作用。
Testosterone deficiency is common in male patients with chronic obstructive pulmonary disease (COPD) and may correlate with the deterioration of COPD. Clinical research suggests that testosterone replacement therapy may slow the COPD progression, but the specific biological pathway remains unclear. In this study, we explored the effect of testosterone on pulmonary inflammation in male COPD rats. The animals were co-treated with lipopolysaccharide (LPS) and cigarette to induce COPD. In COPD rats, nuclear respiratory factor 1 (NRF1) and NF-κB p65 were upregulated. In cigarette smoke extract (CSE)-, LPS-, or the combination of CSE and LPS-treated L132 cells, NRF1 and p65 were also upregulated. Silencing NRF1 resulted in the downregulation of p65. ChIP‒seq, ChIP‒qPCR, and luciferase results showed that NRF1 transcriptionally regulated p65. Both male and female COPD rats showed an upregulated NRF1 level and similar pulmonary morphology. But NRF1 was further upregulated in male castrated rats. Further supplementing testosterone in castrated male rats significantly reduced NRF1, pulmonary lesions, and inflammation. Supplementation of testosterone also reduced the phosphorylation of p65 and IKKβ induced by LPS or CSE in L132 cells. Our results suggest that testosterone plays a protective role in pulmonary epithelial inflammation of COPD through inhibition of NRF1-derived NF-κB signaling and the phosphorylation of p65.
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